The interaction of calmodulin with its target proteins including cyclic nucleotide phosphodiesterase, adenylate cyclase, myoson kinase, phosphorylase kinase, cAMP dependent protein kinase, calcineurin and protein phosphatase has been studied in order to understand the mechanism of regulation of Ca++-dependent cellular processes by this protein. Binding of Ca++ or Tb3+ to specific sites on calmodulin generates stepwise conformational transitions. The different Ca++-dependent interactions of calmodulin with its targets allow calmodulin to effect a kinetic regulation of the Ca++ signal. In contrast to phosphorylase kinase which interacts with calmodulin in the absence of Ca++, phosphodiesterase needs Ca++ for interaction. This enzyme exhibits a highly cooperative Ca++ activation and different degrees of Ca++ occupancy are needed for interaction and activation. Although calmodulin cannot interact simutaneously with more than one protein, different targets recognize and interact with different conformers of the regulatory protein. A third regulatory mechanism involves the interaction of the two second messengers, Ca++ and cAMP. These are closely linked at the level of phosphorylation of the target proteins, regulation of cyclic nucleotide and Ca++ concentrations and also by virtue of interactions between the regulatory subunit of protein kinase and calmodulin.